Prostate cancer can be driven by the same estrogen receptor responsible for the most common form of breast cancer, Weill Cornell Medical College researchers report.
|Dr. Dimple Chakravarty |
Photo credit: Weill Cornell Art & Photography
Their findings suggest why the most aggressive forms of prostate cancer do not respond to traditional therapy. The study also opens up potential for new prognostic biomarkers and treatments, researchers say.
Prostate cancer is thought to be exclusively fueled by male hormones known as androgen (which includes testosterone), which bind on to and turn on androgen receptors to promote growth. For that reason, a common prostate cancer treatment is androgen-deprivation therapy, which cuts the fuel supply of the hormone. But the strategy fails when prostate cancer stops depending on androgen, yet still continues to grow — a phenomenon that has not been understood.
In the study, published Nov. 21 in Nature Communications, the research team discovered that estrogen receptors hijack the androgen-signaling pathway to promote prostate cancer growth.
"The signal to grow comes from the estrogen receptor," says the study's lead investigator, Dr. Dimple Chakravarty, an assistant professor of pathology and laboratory medicine at Weill Cornell.
"The estrogen receptor mimics the androgen receptor pathway, regulating almost all of the genes that are downstream from the androgen receptor," she says. Dr. Chakravarty and her team made the discovery by using next-generation sequencing technology on a Weill Cornell cohort of 74 prostate cancer samples and confirmed the prognostic value of their discovery by analyzing 594 prostate cancer samples shared by the Mayo Clinic. The group was specifically looking for estrogen receptor activity, which had not been examined in such a way before in prostate cancer.
"Men use both hormones — androgen and estrogen — and their levels are physiologically balanced in early and mid-life," Dr. Chakravarty says. "But as men age, the levels of androgen go down and estrogen rises, for reasons that are not understood. We wanted to see what role the estrogen receptor might be playing in prostate cancer."
They looked deeply into RNA molecules that produce proteins, as well as so-called long non-coding RNAs that don’t provide a template for proteins but which control gene expression in ways that are only now beginning to be appreciated, says co-author Dr. Andrea Sboner, a Weill Cornell assistant professor of pathology and laboratory medicine. "These long non-coding RNAs are working in the cell's nucleus, doing more than coding RNAs can do," he says.
Researchers found the estrogen receptor in a significant percentage of samples was activating NEAT1, a known long non-coding RNA. NEAT1, they discovered, drives cancer growth independently of androgen receptor growth. NEAT1 had not been linked to any form of cancer before the study.
The data revealed that estrogen receptor-regulated NEAT1 is the most significantly over-expressed long non-coding RNA in prostate cancer. It is found in both early stage prostate cancer, and in the most aggressive, androgen-resistant cancer, Dr. Chakravarty says, adding that it may be that androgen-deprivation therapy pushes cancer to switch to the estrogen receptor and NEAT1 activation to continue growing.
Because long non-coding RNAs like NEAT1 can be detected in urine, it may be possible to use NEAT1 as a biomarker for the existence of prostate cancer as well as potential prognostic marker, Dr. Sboner says. "The fact that NEAT1 is present in urine may help distinguish men who might need more aggressive treatment from men who have an indolent, slow-growing cancer," he says.
It may be possible to shut down NEAT1 activation with a small molecule inhibitor, Dr. Chakravarty adds. She and her collaborators, which include senior author Dr. Mark Rubin, director of Weill Cornell’s Institute for Precision Medicine, are working on such an agent, and they are continuing to confirm NEAT1’s link to aggressive, androgen-independent prostate cancer.
"This is a new and very exciting way to think about prostate cancer," she says. "Now we have two hormonal culprits to target, instead of one."